1. ¹Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
2. ²The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
3. ³Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4. ⁴Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
5. ⁵Department of Physiology, Dalian Medical University, Dalian, China
6. ⁶Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
7. ⁷Department of Pharmacology, Medical College, National Cheng Kung University, Tainan, Taiwan
8. ⁸Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr J-S Hong, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, MD F1-01, Research Triangle Park, NC, USA. E-mail: hong3@niehs.nih.gov

⁹These authors contributed equally to this work.

Received 21 October 2005; Revised 9 June 2006; Accepted 5 August 2006; Published online 12 September 2006.

Abstract

Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.